Familial hemophagocytic lymphohistiocytosis: a model for understanding the human machinery of cellular cytotoxicity

Abstract

Cytotoxic T lymphocytes, natural killer cells, and NKT cells are effector cells able to kill infected cells. In some inherited human disorders, a defect in selected proteins involved in the cellular cytotoxicity mechanism results in specific clinical syndromes, grouped under the name of familial hemophagocytic lymphohistiocytosis. Recent advances in genetic studies of these patients has allowed the identification of different genetic subsets. Additional genetic immune deficiencies may also induce a similar clinical picture. International cooperation and prospective trials resulted in refining the diagnostic and therapeutic approach to these rare diseases with improved outcome but also with improved knowledge of the mechanisms underlying granule-mediated cellular cytotoxicity in humans.

Fig. 1

NK cell recognizing a target and polarizing its cytoskeleton (tubulin, red) and lytic granules (perforin, green) towards the target. Nuclei are stained blue with Hoechst

Fig. 2

Munc18-2-deficient CTL (FM) with microtubules (green) and perforin granules (red) polarized towards the target. Nuclei are labelled in blue with Hoechst

Fig. 3

Rab27a-deficient patient CTL stained with CD8 (green) recognizing, but not killing a target cell with granules stained with LAMP1 (yellow). The centrosomes and nuclei of both target and killer are stained with g-tubulin (red) and Hoechst (blue)